Effect of Fingolimod on Brain Volume Loss in Patients with Multiple Sclerosis

Abstract

Brain atrophy occurs at a faster rate in patients with multiple sclerosis (MS) than in healthy individuals. In three randomized, controlled, phase III trials, fingolimod reduced the annual rate of brain volume loss (BVL) in patients with relapsing MS (RMS) by approximately one-third relative to that in individuals receiving placebo or intramuscular interferon beta-1a. Analysis of brain volume changes during study extensions has shown that this reduced rate of BVL is sustained in patients with RMS receiving fingolimod continuously. Subgroup analyses of the core phase III and extension studies have shown that reductions in the rate of BVL are observed irrespective of levels of inflammatory lesion activity seen by magnetic resonance imaging at baseline and on study; levels of disability at baseline; and treatment history. The rate of BVL in these studies was predicted independently by T2 lesion and gadolinium-enhancing lesion burdens at baseline, and correlations observed between BVL and increasing levels of disability strengthened over time. In another phase III trial in patients with primary progressive MS (PPMS), fingolimod did not reduce BVL overall relative to placebo; however, consistent with findings in RMS, there was a treatment effect on BVL in patients with PPMS with gadolinium-enhancing lesion activity at baseline. The association between treatment effects on BVL and future accumulation of disability argues in favor of measuring BVL on a more routine basis and with a more structured approach than is generally the case in clinical practice. Despite several practical obstacles, progress is being made in achieving this goal.

Fig. 1

Mean percentage change in BV (measured with SIENA) from day 0 to EOS in FREEDOMS, FREEDOMS II and their extensions [27, 29]. All p values are versus the respective extension study switch group. BV brain volume, EOS end of study, SIENA Structural Image Evaluation, using Normalization, of Atrophy

Fig. 2

Mean percentage change in BV (measured with SIENA) from core study baseline in the continuous and switched groups of patients participating in TRANSFORMS and its extension. In the switched group, patients were switched from IFN beta-1a IM to fingolimod at month 12. Adapted with permission from Cohen et al. [33]. BV brain volume, EOS end of study, IFN beta-1a interferon beta-1a, IM intramuscular, SIENA Structural Image Evaluation, using Normalization, of Atrophy; ***p < 0.001 versus switch group

Fig. 3

Mean percentage change in BV (measured with SIENA) from baseline (core FREEDOMS and FREEDOMS II) in the continuous and switched groups of patients participating in the LONGTERMS extension study [34]. In the switched groups, patients were switched from placebo to fingolimod at month 24. BV brain volume, SIENA Structural Image Evaluation, using Normalization, of Atrophy

Fig. 4

Mean percentage change in BV (measured with SIENA) from baseline in the 2-year FREEDOMS trial, in subgroups of patients with and without gadolinium-enhancing lesions at baseline [35]. BV brain volume, Gd+ gadolinium-enhancing, SIENA Structural Image Evaluation, using Normalization, of Atrophy; *p < 0.05, **p < 0.01, ***p < 0.001 versus placebo

Fig. 5

Relationships between individual outcomes and disability progression in the FREEDOMS trial. Reproduced from Sormani et al. [50]. Pies show the PTE of fingolimod on disability progression at 2 years accounted for by its effect on active T2 lesions at 1 year, on relapses at 1 year, on PBVC at 2 years, and on relapses and PBVC combined, both of which were determined to be independent predictors of disability progression. PBVC percentage brain volume change, PTE proportion of treatment effect